There is a very large unmet therapeutic need to treat humans that abuse illegal drugs, especially cocaine. To address this unmet need, this application is focused on the design, synthesis and pharmacological characterization of potential anti-cocaine medications. Design of new compounds will be based on the structures of several novel leads related to cyclazocine and naltrexone. Cyclazocine is a promising candidate for treating cocaine and heroin abuse because it may decrease dopamine (DA) release in the nucleus accumbens. Naltrexone and related compounds have shown utility in treating heroin abuse, alcoholism and nicotine abuse. We will also design potentially selective kappa antagonists based on the cyclazocine (i.e., benzomorphan) core structure. Kappa antagonists such as JDTic have shown utility preventing stress-induced cocaine relapse in animals. From the drug design perspective, we have found that by replacing the prototypic phenolic-OH group of opiates with a carboxamido (CONHR) group, comparable and, in certain cases, enhanced affinity to opioid receptors is evident. Furthermore, it has been demonstrated that improved pharmacokinetic properties are also seen in certain derivatives. Two important carboxamide-related lead structures have emerged from recent structure-activity relationship (SAR) studies. They are a) the cyclazocine analogue where the 8-OH is replaced by an N-(4'-phenyl)-phenethyl)carboxamido group and b) the naltrexone derivative where the 3-OH group is replaced by a carboxamido group the 4,5alpha-epoxy bridged is reduced giving a 4-OH substituent. Both lead compounds display extremely high affinity for opioid receptors and preliminary SAR studies indicate that kappa selectivity can be seen upon variation of the N-(4'-phenyl)- phenethyl)carboxamido group. An extensive pre-clinical work plan has been put in place based on our expectation that desirable pharmacological and pharmacokinetic profiles will be attained by rational medicinal chemistry design and synthesis. Radioligand binding, [35S]GTPvS, and mouse antinociceptive assays will be used to characterize new targets pharmacologically.